反应详情

温度

35 °C

A solution of 2-{1-[(7-chloro-1,8-naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid (74.9 kg, 175.9 mol), (1S, 2R)-ephedrine hemihydrate (32.5 kg, 186.5 mol), 200 proof ethanol (290 Kg) and water (17 L) were stirred and heated to about 35° C. for 35 minutes. The solution was filtered and then cooled to about 20° C. until the onset of crystallization. The reaction was further cooled to 0-5° C. for about 2 hours. The intermediate ephedrine salt was filtered and washed with a cold (0-5° C.) solution of 200 proof ethanol (206 Kg) and water (10 L). The ephedrine salt was dissolved in 377 L of dichloromethane and stirred with 125 L water and 9.7 kg 37% hydrochloric acid. The aqueous layer was removed. The organic layer was washed with water (125 L). The organic layer was distilled to 60% of the original volume. Carbonyldiimidazole was dissolved in CH2Cl2 (128 L) and slowly transferred to the reaction solution. The reaction was complete after 20 minutes. The reaction was washed two times with water (250 L each). The CH2Cl2 solution was distilled atmospherically, the volume being replaced with of 200 proof ethanol (500 Kg). The ethanol solution was cooled at a rate of 20±5° C. per hour to 0-5° C. The solution was then held at 0-5° C. for 16 hours. The product was filtered and washed with 200 proof ethanol (100 kg). The product was dried for 16 hours under vacuum at 60° C. This afforded 26.0 Kg of (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone as a white solid (36% yield). 1H-NMR: δ 8.87 (d, J=8.8, 1H), 8.61 (m, 2H), 7.93 (d, J=7.0, 1H), 7.74 (m, 4H), 6.05 (m, 1H), 3.62 (m, 1H), 3.28 (dd, J=7.0, 17.2, 1H), 2.42 (m, 2H), 1.35 (m, 3H), 0.79 (d, J=6.2, 6H); CI (MS) M+1 at 408, 100%; [α]D20=+135° (c=1, dichloromethane).

1. filtrationThe solution was filtered
2. temperaturecooled to about 20° C. until the onset of crystallization
3. temperatureThe reaction was further cooled to 0-5° C. for about 2 hours
4. filtrationThe intermediate ephedrine salt was filtered
5. washwashed with a cold (0-5° C.) solution of 200 proof ethanol (206 Kg) and water (10 L)
6. dissolutionThe ephedrine salt was dissolved in 377 L of dichloromethane
7. customThe aqueous layer was removed
8. washThe organic layer was washed with water (125 L)
9. distillationThe organic layer was distilled to 60% of the original volume
10. dissolutionCarbonyldiimidazole was dissolved in CH2Cl2 (128 L)
11. washThe reaction was washed two times with water (250 L each)
12. distillationThe CH2Cl2 solution was distilled atmospherically
13. temperatureThe ethanol solution was cooled at a rate of 20±5° C. per hour to 0-5° C
14. waitThe solution was then held at 0-5° C. for 16 hours
15. filtrationThe product was filtered
16. washwashed with 200 proof ethanol (100 kg)
17. customThe product was dried for 16 hours under vacuum at 60° C